Fluorinated motifs as structural modifications of amides and related N-carbonyl derivatives

This thesis describes the synthesis and examination of properties of N-CF3, N-CF2H and N-CH2F carbonyl derivatives via straightforward approach starting from general building blocks in the form of carbamoyl fluorides. While the synthesis of N-CF3 carbamoyl fluorides has been previously reported, this thesis provides the design and synthesis of two other fluorinated building blocks, i.e. the N-CF2H and N-CH2F carbamoyl fluorides. Additionally, the development of two new methodologies for the synthesis of unprecedented N-CF3 alkynamides and N-CF3 formamides are disclosed. The former relies on mild Ni-catalyzed cross-coupling between N-CF3 carbamoyl fluorides and TMS-alkynes, while the latter utilizies NaBH4 and NaBD4 for facile and robust reduction/deuteration of N-CF3 carbamoyl fluorides. These two methodologies alongside previously developed ones for the derivatization of N-CF3 carbamoyl fluorides were equally effective in the synthesis of broad N-CF2H and N-CH2F carbonyl families starting from corresponding N-CF2H and N-CH2F carbamoyl fluorides, respectively. Studies of the properties of N-CF3, N-CF2H and N-CH2F carbonyl derivatives and their comparison to N-CH3 analogues show a correlation between the lipophilicity and conformational flexibility and the degree of fluorination, with both properties increasing in the trend N-CH3 < N-CH2F < N-CF2H < N-CF3. In this way our methodologies enable the full range of modulation of amides and related carbonyls with regard to fluorination and as such can be beneficial in the development of new drugs, agrochemicals and materials.